Arthritis is an inflammatory disease of the joint, and rheumatoid arthritis and osteoarthritis (or osteoarthrosis) are prevalent arthritic disorders.
Rheumatoid arthritis is thought to be an autoimmune disease, accompanied by articular pain, stiffening and swelling, and as the disease progresses, may often lead to the degeneration of the articular cartilage surfaces similar to osteoarthritis, resulting in severe destruction of the articular bone and cartilage.
Osteoarthritis is a degenerative disease of the articular cartilage occurring frequently in the elderly. Osteoarthritis (OA) involves destruction of the cartilage and proliferative change in the bone and cartilage resulting from degeneration of articular components, with the change resulting in a secondary arthritis (e.g., synovitis). Osteoarthritis occurs mainly in weight-bearing joints, such as the knees, elbows and hip joints (Virchows Arch 1996; 260:521-663), and less frequently in non-weight-bearing joints, such as the shoulder/elbow and hand joints. Furthermore, temporomandibular arthrosis with similar conditions has been identified in the temporomandibular joint (J Orofac Pain 1999; 13(4): 295-306).
It is known that the matrix proteins, which are the functional entity of the cartilage, are reduced, and the number of chondrocytes decreases in osteoarthritis (Arth Rheum 2002; 46(8): 1986-1996). However, due to the lack of blood vessels distributed in the cartilage tissue, the small number of chondrocytes that are highly differentiated, the small number of cartilage precursor cells, and the slow turnover of the cartilage matrix, the cartilage has too low self-reproduction ability to ensure spontaneous recovery from the decreases in articular cartilage matrix and chondrocytes in osteoarthritis (Novartis Found. Symp. 2003; 249:2-16). In addition, in osteoarthritis, arthritis occurs concurrently with the degeneration of cartilage, leading to joint pain (J Rheumatol 2001; 28(6): 1330-1337).
Examples of reported therapeutic/prophylactic agents for arthritis, such as rheumatoid arthritis and osteoarthritis, include, for example, a protein tyrosine kinase inhibitor (Japanese Patent Publication (Kohyo) No. 11-512708A (1999)), N-acyl-2-glucosamine derivatives (Japanese Patent Publication (Kohyo) No. 2004-507490A), and quinoline/quinazoline derivatives (Japanese Patent Publication (Kokai) No. 9-169646A (1997)). In addition, current standard therapeutic agents for osteoarthritis that have been used widely are oral anti-inflammatory analgesics or hyaluronic acid and adrenocortical steroid preparations for intra-articular injection, which all relieve joint pain, and this means that drugs having inhibitory effect on the degeneration of the articular cartilage are required (Decision Base 7, 2002).
Guanyl cyclase (GC) is a membrane protein belonging to the enzyme family that catalyzes the synthesis of the second messenger cGMP from GTP, and examples include GC-A, GC-B, GC-C, GC-D, GC-E, and GC-F. GC-B is found mainly in vascular endothelial cells, and thought to be involved in relaxation of the smooth muscle. A natriuretic peptide (NP) is known to activate GC. NPs are divided into ANP (atrial sodium peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and they are thought to exhibit biological activity by elevating intracellular cGMP level through two guanyl cyclase conjugated receptors (NPR-A for ANP and BNP, and NPR-B for CNP) (Ann Rev Biochem 1991; 60: 229-255).
NPR-C is not a guanyl cyclase conjugated receptor and thought to be a clearance receptor for NPs not involved in signal transduction (Science, 1987; 238:675-678). However, in a system by which prostaglandin E2 (PGE2) production is induced by cyclooxygenase 2 (COX-2) when mouse bone marrow macrophages are stimulated with lipopolysaccharide (LPS), ANP and CNP have been reported to exhibit an inhibitory effect on PGE2 production by decreasing intracellular cAMP levels via NPR-C, and this suggests the involvement of NPR-C in the signal transduction of NPs (Endocrinology 2002; 143(3): 846-852). The report describes that ANP exhibits an inhibitory effect of up to about 70% on the enhancement of PGE2 production through stimulation of mouse bone marrow macrophages (BMM) with LPS, while CNP exhibits only an inhibitory effect of up to about 20%, thus CNP has a weaker effect. Because the control of COX-2 production through cyclic nucleotides, such as cAMP and cGMP, is known to represent either promotional or inhibitory reaction depending on the cell type and stimulation type, it is unclear whether the inhibition of LPS-induced PGE2 production in BMM cells by CNP may be applied to other cells and stimulations. In addition, Endocrinology 2002; 143(3): 846-852 reported that ANP was shown to exhibit an inhibitory effect in a system where LPS administration increased blood thromboxane B2 (TXB2) level in mice, and contrarily cANF of the same mechanism enhanced. In addition, although the report describes the application of ANP to immunity-related diseases, such as arthritis and sepsis, it makes no reference to the application of CNP to those related diseases. Consequently, no finding has been obtained regarding the action of CNP on arthritis.
NPs have been reported to play an important role in the control of humoral homeostasis and blood pressure (J Clin Invest 1987; 93:1911-1921, J Clin Invest 1994; 87: 1402-1412), and their expression and biological activity in various tissues other than the cardiovascular system are known (Endocrinol 1991; 129:1104-1106, Ann Rev Biochem 1991; 60: 553-575). For cartilage, the use of CNP for the extension of auxotonic gristle and treatment of achondrogenesis in transgenic mice overexpressing BNP (Proc. Natl. Acad. Sci. U.S.A. 1998; 95:2337-2342) or CNP has been reported (Nat Med 2004; 10(1): 80-86, Japanese Patent Publication (Kokai) No. 2003-113116A). However, the growth plate cartilage is temporary cartilage that disappears eventually following calcification and displacement by bones, and it is known to have biological properties that are different from permanent cartilage which exists during lifetime, such as articular cartilage and tracheal cartilage (Dev Biol 1989; 136(2): 500-507, J Cell Biol 2001; 153(1): 87-100). Furthermore, although the in vitro activity of CNP to enhance the hypertrophy of articular chondrocytes, which is permanent cartilage, has been reported (J Biol Chem 2003; 278(21): 18824-18832), no finding has been obtained regarding the in vivo action on the articular cartilage in normal animals, or on the degeneration of the articular cartilage or arthritis in osteoarthritis.
In osteoarthritis, the articular cartilage swells at the earliest stage of the disease, resulting in a temporary increase in the cartilage tissue volume (J Rheum 1991; 18(3): 1905-1915), and with the progress of the disease, degeneration/destruction of the cartilage matrix increases, leading to a decrease in the volume (Arthritis Rheum 2004; 50(2): 476-487). The number of articular chondrocytes decreases due to apoptosis (Arthritis Rheum 2004; 50(2): 507-515). On the other hand, the remaining individual articular chondrocytes are known to express type X collagen, and differentiate into hypertrophic chondrocytes having the nature of temporary cartilage (Arthritis Rheum 1992; 35(7): 806-811). In addition, arthritis accompanies the destruction of the articular cartilage and may be a factor in clinical pain in the affected joint (J. Rheumatol. 2001; 28(6): 1330-1337). Inhibition of these changes in osteoarthritis, i.e. the decreases in or recovery of the articular cartilage matrix and the number of articular chondrocytes, and the inhibition of arthritis, is thought to be useful in the development of therapeutic agents.
It is an object of the present invention to provide a new therapeutic or prophylactic agent for arthritis, including osteoarthritis, or a method for treating the arthritis.
It is another object of the present invention to provide an agent or method for promoting the growth of articular chondrocytes.
It is another object of the present invention to provide a method for inhibiting arthritis including osteoarthritis.
It is another object of the present invention to provide a method for screening of a therapeutic agent for arthritis.
It is another object of the present invention to provide a method for screening of an agent for promoting the growth of articular chondrocyte.